Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer

The widely used anti-diabetic drug metformin has been shown to exert strong antineoplastic actions in numerous tumor types, including prostate cancer (PCa). In this study, we show that BI2536, a specific Plk1 inhibitor, acted synergistically with metformin in inhibiting PCa cell proliferation. Furthermore, we also provide evidence that Plk1 inhibition makes PCa cells carrying WT p53 much more sensitive to low-dose metformin treatment. Mechanistically, we found that co-treatment with BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway. Moreover, we also show that BI2536 treatment inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons. Finally, we confirmed the cell-based observations using both cultured cell-derived and patient-derived xenograft studies. Collectively, our findings support another promising therapeutic strategy by combining two well tolerated drugs against PCa proliferation and the progression of androgen-dependent PCa to the castration-resistant stage

Generation of dual-gRNA library for combinatorial CRISPR screening of synthetic lethal gene pairs

Combinatorial CRISPR screening is useful for investigating synthetic lethality (SL) gene pairs. Here, we detail the steps for dual-gRNA library construction, with the introduction of two backbones, LentiGuide_DKO and LentiCRISPR_DKO. We describe steps fo

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism

High Quality Plasmonic Sensors Based on Fano Resonances Created through Cascading Double Asymmetric Cavities

In this paper, a type of compact nanosensor based on a metal-insulator-metal structure is proposed and investigated through cascading double asymmetric cavities, in which their metal cores shift along different axis directions. The cascaded asymmetric structure exhibits high transmission and sharp Fano resonance peaks via strengthening the mutual coupling of the cavities. The research results show that with the increase of the symmetry breaking in the structure, the number of Fano resonances increase accordingly. Furthermore, by modulating the geometrical parameters appropriately, Fano resonances with high sensitivities to the changes in refractive index can be realized. A maximum figure of merit (FoM) value of 74.3 is obtained. Considerable applications for this work can be found in bio/chemical sensors with excellent performance and other nanophotonic integrated circuit devices such as optical filters, switches and modulators

Flame sprayed environmentally friendly high density polyethylene (HDPE)-capsaicin composite coatings for marine antifouling applications

Flame sprayed environmentally friendly high density polyethylene (HDPE)-capsaicin composite coatings for marine antifouling application

Symptom and comorbidity burden in hypertensive patients with obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) is an important but frequently overlooked risk factor for hypertension (HTN). The prevalence of hypertension is high in patients with OSA, but the differences in clinical symptoms and comorbidities between patients with OSA with hypertension and those with normal blood pressure have not been fully defined.MethodsThis study retrospectively analyzed OSA patients diagnosed for the first time in Lihuili Hospital Affiliated to Ningbo University from 2016 to 2020. Patients were divided into an OSA group with hypertension and an OSA group without hypertension. The sociodemographic information, clinical symptoms, comorbidities, and polysomnography results of the two groups were compared. The independent risk factors associated with hypertension in patients with OSA were explored.ResultsA total of 1108 patients with OSA initially diagnosed were included in the study, including 387 with hypertension and 721 without. Compared with OSA patients without hypertension, OSA patients with hypertension were older; had a higher body mass index (BMI) and Epworth sleepiness score (ESS); a higher incidence of nocturia; and a higher proportion of diabetes mellitus, coronary heart disease, and cerebrovascular disease. Multivariate analysis showed age (odds ratio [OR]:1.06, 95% confidence interval [CI]:1.04-1.08), BMI (OR:1.17, 95% CI:1.11-1.23), ESS score (OR:0.97, 95%CI: 0.94-1.00) and nocturia symptoms (OR:1.64, 95% CI:1.19-2.27) was independently associated with hypertension in OSA patients, and comorbid diabetes (OR: 3.86, 95% CI: 2.31-6.45), coronary heart disease (OR: 1.90, 95% CI:1.15-3.16), and ischemic stroke (OR: 3.69,95% CI:1.31-10.40) was independently associated with hypertension in OSA patients.ConclusionCompared to OSA patients with normal blood pressure, OSA patients with hypertension had more significant daytime sleepiness, more frequent nocturnal urination, and a higher risk of diabetes, coronary heart disease, and cerebrovascular disease

Microgrids as Flexible and Network-Connected Grid Assets in Active Distribution Systems

The functionalities of microgrids are detailed and thereby expanded in active distribution systems. A versatile and coordinated operation among multiple microgrids is proposed to facilitate the integration of renewable energy sources (RES) in modern distribution grids. Particularly, to meet the requirements of high penetration level of renewables (e.g., photovoltaics and small hydro), more than one networked controlled microgrids are deployed simultaneously in different locations of a distribution system. Therefore, local RES can be aggregated in each microgrids. In order to satisfy the latest standards in terms of renewable energy integration (i.e., IEEE Std. 1547 Rev), an optimal operation strategy is designed to coordinate the operation of multiple microgrids. A simulation model is implemented in MATLAB to validate the proposed networked microgrids and the corresponding operation strategy

Methylation of 45S Ribosomal DNA (rDNA) Is Associated with Cancer and Aging in Humans

Cancer and aging, two distinct processes of cell development, are two major problems threatening our human health and life in current days. Epigenetic studies, especially DNA methylation, have been intensively investigated on them over the years, though a lot of unanswered issues remain. In the human genome, rDNA is a highly conserved tandem repeat family playing critical roles in protein synthesis, genome stability and integrity, etc. More importantly, rDNA is the significant target of DNA methylation, and a potential association between rDNA methylation and cancer and aging has emerged recently. However, whether there is a general trend that rDNA methylation is associated with cancer and aging remains an open issue. In this study, the involvement of rDNA methylation in a series of records of cancer and aging was investigated and summarized, upon which perspectives about rDNA methylation in cancer and aging were proposed. The results showed that rDNA methylation in most cancer cases displayed a consistent pattern with hypermethylation in the coding region but with hypomethylation in the promoter region, which likely facilitates the proliferation and metastasis of cancerous cells. Distinctively, both the coding and promoter regions of rDNA become increasingly methylated during the process of aging, indicating the decline of rDNA activity. The finding of rDNA methylation also implies its potential application as an epigenetic biomarker in the diagnosis of cancer and aging. This work will shed light on our understanding of the pathogenesis, diagnosis, and treatment of cancer and aging from the perspective of rDNA methylation